Brazilian Protocol for Sexually Transmitted Infections 2020: human T-cell lymphotropic virus (HTLV) infection

Abstract This article addresses the Human T-lymphotropic virus (HTLV). This subject comprises the Clinical Protocol and Therapeutic Guidelines for Comprehensive Care for People with Sexually Transmitted Infections, published by the Brazilian Ministry of Health. HTLV-1/2 infection is a public health problem globally, and Brazil has the largest number of individuals living with the virus. HTLV-1 causes several clinical manifestations of neoplasm (adult T-cell leukemia/lymphoma) and inflammatory nature, such as HTLV-1-associated myelopathy and other manifestations such as uveitis, arthritis, and infective dermatitis. These pathologies have high morbidity and mortality and negatively impact the quality of life of infected individuals. This review includes relevant information for health authorities professionals regarding viral transmission, diagnosis, treatment, and monitoring of individuals living with HTLV-1 and 2 in Brazil.

Proviral load levels correlate with the progression of the disease, especially with muscle weakness. Although the magnitude of the proviral load in peripheral blood is associated with HAM, it is not the sole diagnostic or prognostic factor of the pathology 84 . Proviral load in cerebrospinal fluid is important to define the progression of HAM since HTLV-1 infected cells in the central nervous system accelerate the local inflammatory process 26, [85][86][87] . However, other prognostic value markers should be evaluated to identify people at higher risk of illness [88][89][90] .
ADULT T-CELL LEUKEMIA/LYMPHOMA The neoplasm of peripheral T-cells caused by HTLV-1 presents itself with leukocytosis, characterized by the presence of abnormal lymphocytes (flower cells) and, clinically, by lymphadenopathies, skin lesions, dysfunction of multiple organs resulting from the invasion of the neoplastic cells, in addition to the presence of opportunistic infections. Elevated levels of the enzyme lactate dehydrogenase and hypercalcemia are characteristic. In Japan, there are over one million carriers and the incidence of ATL varies from 0.6 to 0.7 per 1000 persons/year 91 . The risk of illness is higher in men, and symptoms begin 20 to 30 years after infection 92 . Rarely, ATL occurs before 30 years of age; however, its frequency tends to increase to reach those with 70 years of age. In Japan, where the probability of developing ATL is 5%, risk factors are: (i) maternal transmission, (ii) older age, (iii) increased proviral load in peripheral blood, (iv) family history of ATL, and (v) prior positive testing for anti-HTLV-1 93,94 . ATL is rare in other countries, not reaching 2% of cases 95 , despite evidence of lack of diagnosis 96,97 .
Four clinical forms of ATL are recognized 98 , which take into account the presence and severity of the leukemic manifestations, in addition to altered laboratory tests, such as increased lactate dehydrogenase and hypercalcemia. This classification is described in Figure 1, and the factors that predict worse prognosis, including those mentioned above, are found in Figure 2 51,[98][99][100][101] .

DERMATOLOGICAL ALTERATIONS IN INDIVIDUALS WITH HTLV
In addition to the clinical manifestations classically associated with HTLV-1 in the skin, such as infective dermatitis and the   Note: a) Need for intrathecal chemotherapy.

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cutaneous manifestations of ATL, other dermatological affections attributed to the infection have been described as serious forms of scabies (especially in HIV-1 coinfected individuals) 102 , ichthyoses, seborrheic dermatitis, and dermatophytoses 103 .
At first, infective dermatitis was described in Jamaican children infected by HTLV-1 104 , mainly when vertical transmission occurs, although the disease can also affect adolescents and adults 105 . Infective dermatitis is characterized by erythematous-desquamative lesions, which generally involve the scalp, retro auricular regions, neck, face, armpits, and inguinal region. Typically, it is associated with infection by Gram-positive bacteria such as Streptococcus beta-hemoliticus and Staphylococcus aureus. According to a case series study, almost half of the individuals who had long-term follow-up were also diagnosed with HAM 106 . The differential diagnosis includes other causes of chronic eczemas, such as atopic dermatitis and seborrheic dermatitis 106 . Presence of the characteristic lesions, chronic rhinorrhea, recurrent chronic dermatitis, and positive serology for HTLV are the main criteria for diagnosing infective dermatitis, whose treatment consists of administering antibiotics with topical use of corticosteroids, combined or not with antifungals.
Dermatological alterations in ATL vary in presentation (erythroderma, papules, nodules, infiltrating lesions, or erythematous plaques) and depend on the disease stage; nodulations are more frequent in severe forms, especially in the acute, lymphomatous, or cutaneous primary tumoral form 107 . The lesions may evolve indolently and modify with the use of corticosteroids. Histopathological evaluation is essential for specific diagnosis.

UVEITIS IN INDIVIDUALS WITH HTLV-1
In Japan, uveitis was first reported in 1989 108 . Most common in people in age up to 50 years and a little more frequent in women, its exact incidence among HTLV-1 carriers remains uncertain. The disease is manifested by visual disorders, including 'floaters' and blurred or hazy vision, and it is bilateral in almost half of the affected people 109 . Eye signs include iritis, vitreous opacities, retinal vasculitis, and retinal hemorrhages and exudates. There is a good patient response to topical or systemic corticosteroids, although recurrence is common with therapy discontinuation.

COINFECTIONS IN INDIVIDUALS WITH HTLV
HTLV-infected individuals may present some coinfections, more frequently than the general population, either by sharing infection routes or as a consequence of the immunological alterations induced by the infection itself. Moreover, HTLV can alter the natural course of some coinfections.
In HIV coinfection, for example, the evidence suggests a neutral or even protective role for those coinfected by HTLV-2 110 . However, if the coinfection is HIV-1/HTLV-1, the existing data show a higher risk of death, both in adults and in children 111 . The reasons for these findings are not very clear. A hypothesis for the lack of clinical benefit is the delay in introducing the antiretroviral therapy due to the increase in the T-CD4 + cells count caused by HTLV-1. Coinfected individuals treated with antiretroviral therapy and with HIV-1 viral suppression present similar survival time to those monoinfected under the same conditions; however, in those with a detectable viral load, the survival of coinfected individuals is significantly lower 112 .
Regarding coinfection with hepatitis C virus (HCV), existing data are conflicting: while some studies show an increase in HCV viremia and a lower probability of spontaneous clearance of the infection 113 , others suggest a higher chance of elimination of this virus in HIV-1 and HTLV-coinfected individuals, probably due to the immunomodulation caused by HTLV in this group of individuals, resulting from the high production of proinflammatory cytokines 114 . Moreover, studies are suggesting less hepatic damage in triple infected individuals -with HIV, HTLV, and HCV-and a greater chance of spontaneous clearance of HCV 115,116 .

DIAGNOSIS
In Brazil, routine testing for HTLV-1/2 in blood and organ donors has been performed since 1993 and 2009, respectively 42, 133 . In both cases, the infection is a criterion for donor exclusion. Although there is no national policy for HTLV-1/2 antenatal screening in Brazil, the test is done as a routine in some states. The MS/SCTIE Portaria no. 23, of May 31, 2016, included the Western blot (Wb) test and the polymerase chain reaction (PCR) to confirm HTLV-1 infection among patients suspected of ATL assisted by the Brazilian National Health System (SUS) 134 . Figure 3 shows the indications for HTLV-1/2 testing. Laboratory diagnosis must be performed using screening tests, followed by confirmatory tests in a different blood sample when screening test results are positive [135][136][137] (Figure 4).
The screening tests are used for detecting antibodies against HTLV-1/2 in plasma or serum. The laboratory techniques for performing these tests include (i) immunoenzymatic reaction, (ii) chemiluminescence, and (iii) particle agglutination 136 . The screening tests present high sensitivity. The negative result excludes infection -unless there is evidence of recent exposure to the virus when it is recommended to repeat the test after 90 days 24,25 . The specificity of screening tests in Brazil varies from 92 to 99.5%. It is highly recommended to perform confirmatory tests to exclude false-positive results in the screening tests [136][137][138] .
The confirmatory tests identify antibodies against different HTLV-1 and HTLV-2 antigens or amplify and identify proviral genetic material, usually in peripheral blood lymphocytes. Confirmatory and viral typing tests are (i) Wb, (ii) line immunoassay (LIA), and (iii) PCR 136 .
Usually, Wb and LIA are sufficient for diagnosis; however, in some cases, undetermined or undefined results may occur regarding   the type of HTLV [139][140][141][142][143][144][145][146][147][148][149] , more frequently in individuals infected by HTLV-2 or HIV-1 or both 141,150 . LIA presents greater accuracy in confirming HTLV-1 and HTLV-2 infection when compared to Wb 151,152 . Indeterminate or untyped results by Wb or LIA must be submitted to qualitative or quantitative PCR: nested PCR (nPCR) and real-time PCR (RT-PCR) are used. RT-PCR enables not only the quantification of the HTLV-1/2 proviral load but also the stratification of the risk of developing HTLV-1 associated diseases 26, 93,94,142,[153][154][155] . The detection of viral RNA is not used in the clinical routine, since viremia is low or absent, even in individuals with HAM 156,157 .
At the time of this publication, a molecular test for HTLV-1/2 is not commercially available. The tests used are in-house, requiring prior validation 155,158-161 . The absence of commercial tests and standardization of national protocols makes the implementation of molecular testing in the routine and the comparison of results obtained in different laboratories difficult 162,163 . Some individuals infected by HTLV-1/2 may present undetectable proviral load [164][165][166] . In these cases, it is possible to perform nPCR of higher sensitivity than RT-PCR. Another alternative is to perform a confirmatory serological test (if not yet performed) or to request consecutive samples for follow-up 148 .
There is evidence that the duration of the immunological window period in HTLV-1/2 infection for antibody detection varies from 16 to 39 days after organ transplantation, and for the proviral genetic material, from 16 to 23 days after infection 167 . A study conducted with individuals infected by blood transfusion showed a median seroconversion of 51 days (36 to 72 days) 25 . It is important to emphasize that the methodologies available when this study was developed did not have the same sensitivity as the current diagnostic methods 168 . Infected people must be accompanied in the specialized service to receive psychological support, with particular attention to the early diagnosis of clinical manifestations associated with the infection.

SURVEILLANCE, PREVENTION, AND CONTROL
Despite being described some decades ago, HTLV infection remains relatively unknown to the general population and health professionals. In the services that assist the infected individuals, the approach should focus not only on the aspects of the risk of becoming sick 173 but also on preventing the transmission of infection.
After a positive diagnosis for HTLV-1/2 infection, the sexual partners should be invited to undergo serological screening, and those with positive tests must be referred for counseling and appropriate follow-up. Such counseling should include information about the chronicity of the infection and the relevance of long-term clinical follow-up 169,174 . It is important to clarify the initial clinical manifestations and their progression, the transmission mechanisms, and their prevention. The donation of blood, semen, solid organs or tissues and breastfeeding are strongly discouraged.
In HIV and other STI specialized clinical centres, it is important to include HTLV screening in the routine of care. HTLV-infected individual must be oriented about the risk of sexual transmission, serodiscordant sexual partners, and condom use -which may be interrupted during the fertile period when there is a firm decision to become pregnant and following medical counselling and recommendation 174 .
In Brazil, given the scarcity of material available for health professionals and the general population, several initiatives have been developed by academic groups and non-governmental organizations to disseminate information about HTLV-1/2. Among the organizations and initiatives with this purpose, the following should be highlighted: the Research Support Center on Retroviruses (NAP-Retroviruses) of the University of São Paulo; the Hemominas Foundation Journals on HTLV infection; the HTLVida Association; and the Vitamóre Group -Association of HTLV Carriers.
The lack of a national register system impairs the identification of the actual scenario of the infection in the country and, therefore, the implementation of specific public health policies. It is essential to highlight that case notification is one of the pillars of confrontation and research about HTLV-1 in countries like Japan, England, Spain, and Martinique island [175][176][177][178] .
Since breastfeeding is the main mother to child transmission route of HTLV-1/2 135,[199][200][201][202][203][204] and there is no vaccine against the infection or even any curative treatment, breastfeeding is contraindicated in mothers infected by the virus. For these women, the use of lactation inhibitors is recommended and the provision of infants with milk formula substitutes 2 . Universal antenatal HTLV-1/2 infection screening is not provided by the SUS, but it is recommended to test all pregnant women, followed by counselling for those infected and their relatives, allowing the effective implementation of prevention strategies.

Indigenous peoples
The vertical and sexual transmission routes are essential for HTLV maintenance in epidemiologically closed or semi-closed communities, as it occurs with HTLV-2c, which is prevalent among indigenous people residing in the Brazilian Amazon and urban areas 12,13,[205][206][207][208][209] . It is worth remembering that intrafamiliar infection in the Kayapó communities is important and it is observed the transmission of the virus between two or three generations and in more than 20% of infected children under nine years old 12 . Vertical transmission maintains the virus in high endemicity since the usual nonbreastfeeding procedures by infected mothers are not followed regularly 205 . The increasing number of reports associating diseases with HTLV-2 5,43-48 infections requires special attention to the indigenous communities located in areas of high virus endemicity in the Brazilian Amazon 39 .

CONCLUSIONS
Although HTLV infection is neglected, Brazil has produced several initiatives directed towards the prevention of HTLV-1 infection and disease. The complications with relevant clinical consequences, such as HTLV-1 associated myelopathy and T-cell leukemia/lymphoma, can be minimized with access to services offered by the SUS. The low complexity cases can be assisted at the health centers and, when necessary, forwarded to the specialized centers for treatment, rehabilitation, and social support. Despite the severe consequences that the infection can have on people's lives, its control still represents a public health challenge. National epidemiological studies, development and validation of diagnostic tests, and elaboration of clinical protocols with new therapeutic options can define public policies and specific actions towards the approach, prevention, control, and adequate treatment of HTLV-1/2 infection in Brazil.